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Stress-activated kinases as therapeutic targets in pancreatic cancer

World Journal of Gastroenterology 2021年第30期27卷 4963-4984页

作者： Benno Traub Aileen Roth Marko Kornmann Uwe Knippschild Joachim Bischof Department of General and Visceral Surgery Ulm University HospitalUlm 89081Germany

Pancreatic cancer is a dismal disease with high incidence and poor survival *** the aim to improve overall survival of pancreatic cancer patients,new therapeutic approaches are urgently *** kinases are key regulatory players in basically all stages of development,maintaining physiologic functions but also being involved in pathogenic processes.c-jun n-terminal kinases(JnK)and p38 kinases,representatives of the mitogen-activated protein kinases,as well as the casein kinase 1(cK1)family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors,DnA damage,and *** their physiologic roles,they are responsible for the regulation of cell cycle progression,cell proliferation and differentiation,and *** of the underlying pathways consequently has been identified in various cancer types,including pancreatic *** targeting of those pathways has been the field of interest for several *** success in earlier studies was limited due to lacking specificity and off-target effects,more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro ***,targeting of JnK,p38,and cK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these ***,further studies are warranted,especially involving in vivo investigation and clinical trials,in order to advance inhibition of stress-activated kinases to the field of translational medicine.

关键词： Pancreatic cancer Stress-activated protein kinases Mitogen-activated protein kinases c-jun n-terminal kinases casein kinase 1 Small molecule inhibitor

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Sodium valproate induces mitochondria-dependent apoptosis in human hepatoblastoma cells

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chinese Medical Journal 2011年第14期124卷 2167-2172页

作者： WAnG Wei LIAO Xiao-li cHEn Jing-hong LI Dan-dan LIn chun-lan YAn Yu-xia TAnG Yu-hui JIAnG Jian-wei Department of Biochemistry Medical College of Jinan UniversityGuangzhou Guangdong 510632 China State Key Laboratory of Oncology in Southern china Cancer Center Sun Yat-sen University Guangzhou Guangdong 510060China Department of Biochemistry Guangzhou University of Chinese Medicine Guangzhou Guangdong 510006 China

Background Sodium valproate inhibits proliferation in neuroblastoma and glioma cells, and inhibits proliferation and induces apoptosis in hepatoblastoma cells. Information describing the molecular pathways of the antitumor effects of sodium valproate is limited; therefore, we explored the mechanisms of action of sodium valproate in the human hepatoblastoma cell line, *** The effects of sodium valproate on the proliferation of HepG2 cells were evaluated by the Walsh-sohema transform and colony formation assays. Sodium valproate-induced apoptosis in HepG2 cells was investigated with fluorescence microscopy to detect morphological changes; by flow cytometry to calculate DnA ploidy and apoptotic cell percentages; with Western blotting analyses to determine c-jun n-terminal kinases （JnK）, p-JnK, Bcl-2, Bax, and caspase-3 and-9 protein expression levels; and using Jc-1 fluorescence microscopy to detect the membrane potential of mitochondria. Statistical analyses were performed using one-way analysis of variance by SPSS 13.0 *** Our results indicated that sodium valproate treatment inhibited the proliferation of HepG2 cells in a dose-dependent manner. Sodium valproate induced apoptosis in HepG2 cells as it： caused morphologic changes associated with apoptosis, including condensed and fragmented chromatin; increased the percentage of hypodiploid cells in a dose-dependent manner; increased the percentage of annexin Ⅴ-positive/propidium iodide-negative cells from 9.52％ to 74.87％; decreased JnK and increased phosphate-JnK protein expression levels; reduced the membrane potential of mitochondria; decreased the ratio of Bcl-2/Bax; and activated caspases-3 *** Sodium valproate inhibited the proliferation of HepG2 cells, triggered mitochondria-dependent HepG2 cell apoptosis and activated JnK.

关键词： hepatoblastoma sodium valproate c-jun n-terminal kinases mitochondria apoptosis

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neuronal effects of SP600125 pretreatment in a rat model of cerebral ischemia/reperfusion injury Inhibited down-regulation of DnA repair protein

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neural Regeneration Research 2009年第12期4卷 1055-1061页

作者： ning Wang Rongliang Xue Fengzhen Yao Jiaxuan He Jianrui Lu Pengbo Zhang Gang Wu Department of Anesthesiology Second Affiliated Hospital Xi'an Jiaotong University Xi'an 710004 Shaanxi province China Department of Anesthesiology Jiangsu Province Hospital of Traditional Chinese Medicine Nanjing 210002 Jiangsu province China

BAcKGROUnD： Recent studies have shown that the selective inhibitor of c-jun n-terminal kinases （JnKs） signaling pathway, SP600125, exhibits neuronal protective effects in a rat model of brain ischemia/reperfusion. OBJEcTIVE： To determine the mechanisms of neuroprotective effects of SP600125 in a rat model of brain ischemia/reperfusion, and determine the role of the JnK signaling pathway in SP600125-induced effects. DESIGn, TIME AnD SETTInG： A randomized, controlled, animal experiment was performed at the Animal Experiment center, Medical School of Xi＇an Jiaotong University from june 2007 to September 2008. MATERIALS： SP600125 was provided by Biosource, USA; rabbit anti-phospho-JnK （Thr183/Tyr185） polyclonal antibody from cell Signaling Technology, USA; rabbit anti-X-ray repair cross-complementing protein 1 （XRcc1） and anti-Ku70 polyclonal antibodies from Santa cruz Biotechnology, USA; and TUnEL kit from Beijing Huamei Biology, china. METHODS： A total of 108 male, 4-month-old, Sprague Dawley rats were randomly assigned to three groups, with 36 rats per group. The sham operation group and ischemia/reperfusion group （I/R group） were intracerebroventricularly injected with 10 μL 1% DMSO. The SP600125-treated group （pre-SP group） was given 10 μL SP600125 （3 μg/μL）. Thirty minutes later, brain ischemia was induced in the I/R and pre-SP groups using the four-vessel occlusion method. Specifically, whole brain ischemia was induced for 6 minutes, and the clips were released to restore carotid artery blood flow. Rats from each group were observed at 2, 6, 12, 24, 48, and 72 hours, with 6 rats for each time point. The sham operation group was treated with the same surgical exposure procedures, with exception of occlusion of the carotid artery. MAIn OUTcOME MEASURES： Hematoxylin-eosin staining was used to observe neuronal survival in the hippocampal cA1 region, TUnEL was used to detect apoptosis in the hippocampal cA1 region, and immunohistochemistry was used to detect expressio

关键词： ischemia/reperfusion injury apoptosis c-jun n-terminal kinases DnA repair protein X-ray repair cross-complementing protein 1 Ku70

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